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Peer-reviewedCC BY-NC-NDBlood neoplasia

TCL1A polymorphism predicts AML progression in myeloid neoplasms

  • Alfonso Molina1
  • Jayakrishnan Gopakumar2
  • Alexandria Jensen3
  • Vishesh Khanna1
  • Henning Stehr2
  • Siddhartha Jaiswal2
  • Peter L. Greenberg1
  1. 1Hematology Division, Department of Medicine, Stanford University School of Medicine, Stanford, CA
  2. 2Department of Pathology, Stanford University School of Medicine, Stanford, CA
  3. 3Quantitative Sciences Unit, Stanford University, Stanford, CA
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Abstract

Variable risks of acute myeloid leukemia (AML) progression of myeloid malignancies are dependent upon their mutational and clinical features. A common TCL1A gene promoter polymorphism (rs2887399-T allele, G/T or T/T) reduces TCL1A expression and fitness for expansion of TCL1A-linked mutations recurrently found in MDS and CMML (TET2, ASXL1, SF3B1, SRSF2, IDH1/2, JAK2) compared to those with the G/G-allele (wild type). We analyzed 208 MDS and CMML patients who underwent targeted next generation sequencing of myeloid malignancy genes and rs2887399 genotyping. Primary analysis for evaluating AML-progression-free survival (PFS) and the cumulative incidence of AML progression compared patients with TCL1A-linked mutations plus the rs2887399-T allele to those with these mutations plus the wild type rs2887399-G/G genotype. Among patients with TCL1A-linked mutations (119/208, 57%), rs2887399-T carriers (n = 35) had lower 3-year AML progression (2.9% vs 18%, p = .037), longer AML PFS (96.4% vs 79.8%, P = .039) and lower cumulative incidence of AML (2.9% vs 17.3%, P = .006) than G/G carriers (n = 84), despite similar molecular risk. Multivariable Cox analysis showed reduced AML progression hazard in TCL1A-linked rs2887399-T carriers versus the TCL1A-linked-G/G and non-TCL1A-linked-T (HR 0.26, 95% CI 0.06-0.88, p=0.029). In conclusion, the rs2887399-T allele diminished and delayed AML evolution in MDS/CMML patients with TCL1A-linked mutations. These data support the concept that the TCL1A polymorphism in the setting of specific somatic mutations is a modulator of leukemogenesis, providing potential utility of such germline genotyping for disease risk stratification.

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Cite

BibTeXRIS
BibTeX
@article{molina2026tcl1a,
  title = {{TCL1A polymorphism predicts AML progression in myeloid neoplasms}},
  author = {Alfonso Molina and Jayakrishnan Gopakumar and Alexandria Jensen and Vishesh Khanna and Henning Stehr and Siddhartha Jaiswal and Peter L. Greenberg},
  journal = {Blood neoplasia},
  year = {2026},
  month = aug,
  doi = {10.1016/j.bneo.2026.100290},
  url = {https://europepmc.org/article/PMC/PMC13718587},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - TCL1A polymorphism predicts AML progression in myeloid neoplasms
AU  - Alfonso Molina
AU  - Jayakrishnan Gopakumar
AU  - Alexandria Jensen
AU  - Vishesh Khanna
AU  - Henning Stehr
AU  - Siddhartha Jaiswal
AU  - Peter L. Greenberg
PY  - 2026
DA  - 2026/08/24
JO  - Blood neoplasia
DO  - 10.1016/j.bneo.2026.100290
UR  - https://europepmc.org/article/PMC/PMC13718587
AB  - Variable risks of acute myeloid leukemia (AML) progression of myeloid malignancies are dependent upon their mutational and clinical features. A common TCL1A gene promoter polymorphism (rs2887399-T allele, G/T or T/T) reduces TCL1A expression and fitness for expansion of TCL1A-linked mutations recurrently found in MDS and CMML (TET2, ASXL1, SF3B1, SRSF2, IDH1/2, JAK2) compared to those with the G/G-allele (wild type). We analyzed 208 MDS and CMML patients who underwent targeted next generation sequencing of myeloid malignancy genes and rs2887399 genotyping. Primary analysis for evaluating AML-progression-free survival (PFS) and the cumulative incidence of AML progression compared patients with TCL1A-linked mutations plus the rs2887399-T allele to those with these mutations plus the wild type rs2887399-G/G genotype. Among patients with TCL1A-linked mutations (119/208, 57%), rs2887399-T carriers (n = 35) had lower 3-year AML progression (2.9% vs 18%, p = .037), longer AML PFS (96.4% vs 79.8%, P = .039) and lower cumulative incidence of AML (2.9% vs 17.3%, P = .006) than G/G carriers (n = 84), despite similar molecular risk. Multivariable Cox analysis showed reduced AML progression hazard in TCL1A-linked rs2887399-T carriers versus the TCL1A-linked-G/G and non-TCL1A-linked-T (HR 0.26, 95% CI 0.06-0.88, p=0.029). In conclusion, the rs2887399-T allele diminished and delayed AML evolution in MDS/CMML patients with TCL1A-linked mutations. These data support the concept that the TCL1A polymorphism in the setting of specific somatic mutations is a modulator of leukemogenesis, providing potential utility of such germline genotyping for disease risk stratification.
SN  - 2950-3280
ER  -